A uniform effect of DNA intercalating agents is the production of protein-associated DNA scission in mammalian cells following their exposure to these drugs. The precise biochemistry of this effect and its relation to drug effects on a host of biochemistry events is unknown. We have shown that the production of this effect has several characteristics of an enzymatic process including saturability, temperature-dependence and reversibility. In the past year we have enhanced our understanding of the relationship of this DNA scission to drug-induced cytotoxicity, to the cell cycle phase at the time of intercalator treatment, to hormonal effects on cellular chromatin and to specific alterations in 2- and 3-dimensional chromatin structure. In addition, partial purification of the enzymatic activity producing the DNA scission has been accomplished and a totally in vitro system for reconstituting and thus characterizing this novel effect now exists. Finally, a clinical trial for the treatment of acute nonlymphocytic leukemia has been initiated which utilizes the principles discovered in our laboratory as well as the results of a completed phase I-II trial of continuous infusion m-AMSA.